Scorpionfish BPI is highly active against multiple drug-resistant Pseudomonas aeruginosa isolates from people with cystic fibrosis
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eLife assessment
In this useful study, Holzinger et al. present compelling evidence that scorpionfish bactericidal/permeability-increasing protein (scoBPI) exhibits remarkable antibacterial activity against multi-drug resistant Pseudomonas aeruginosa. These findings open new avenues of research for identifying novel chemotherapies to treat Pseudomonas infections and have broader implications in developing chemotherapies against other drug-resistant Gram-negative bacterial infections. The work will be of interest to individuals investigating novel cystic fibrosis antimicrobials.
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Abstract
Chronic pulmonary infection is a hallmark of cystic fibrosis (CF) and requires continuous antibiotic treatment. In this context, Pseudomonas aeruginosa ( Pa ) is of special concern since colonizing strains frequently acquire multiple drug resistance (MDR). Bactericidal/permeability-increasing protein (BPI) is a neutrophil-derived, endogenous protein with high bactericidal potency against Gram-negative bacteria. However, a significant range of people with CF (PwCF) produce anti-neutrophil cytoplasmic antibodies against BPI (BPI-ANCA), thereby neutralizing its bactericidal function. In accordance with literature, we describe that 51.0% of a total of 39 PwCF expressed BPI-ANCA. Importantly, an orthologous protein to human BPI (huBPI) derived from the scorpionfish Sebastes schlegelii (scoBPI) completely escaped recognition by these autoantibodies. Moreover, scoBPI exhibited high anti-inflammatory potency towards Pa LPS and was bactericidal against MDR Pa derived from PwCF at nanomolar concentrations. In conclusion, our results highlight the potential of highly active orthologous proteins of huBPI in treatment of MDR Pa infections, especially in the presence of BPI-ANCA.
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eLife assessment
In this useful study, Holzinger et al. present compelling evidence that scorpionfish bactericidal/permeability-increasing protein (scoBPI) exhibits remarkable antibacterial activity against multi-drug resistant Pseudomonas aeruginosa. These findings open new avenues of research for identifying novel chemotherapies to treat Pseudomonas infections and have broader implications in developing chemotherapies against other drug-resistant Gram-negative bacterial infections. The work will be of interest to individuals investigating novel cystic fibrosis antimicrobials.
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Reviewer #1 (Public Review):
Holzinger et al. investigated potential antimicrobial compounds for cystic fibrosis (CF) infection with similarity to a host-derived antimicrobial, bactericidal permeability-increasing protein (BPI). Human BPI (huBPI) is neutralised by anti-BPI antibodies, rendering it ineffective at eradicating Pseudomonas aeruginosa infection in a large proportion of people with cystic fibrosis. BPI produced by mice (muBPI), scorpionfish (scoBPI), and oysters (oyBPI) was evaluated on their anti-inflammatory, bactericidal, and immunogenic potency. The authors showed that each BPI orthologue evaded recognition by anti-BPI. The cationic BPI orthologues also reduced bacterial burden in vitro, reducing the expression of proinflammatory cytokines (IL-6 and TNF) and significantly decreasing cell culture density in the laboratory …
Reviewer #1 (Public Review):
Holzinger et al. investigated potential antimicrobial compounds for cystic fibrosis (CF) infection with similarity to a host-derived antimicrobial, bactericidal permeability-increasing protein (BPI). Human BPI (huBPI) is neutralised by anti-BPI antibodies, rendering it ineffective at eradicating Pseudomonas aeruginosa infection in a large proportion of people with cystic fibrosis. BPI produced by mice (muBPI), scorpionfish (scoBPI), and oysters (oyBPI) was evaluated on their anti-inflammatory, bactericidal, and immunogenic potency. The authors showed that each BPI orthologue evaded recognition by anti-BPI. The cationic BPI orthologues also reduced bacterial burden in vitro, reducing the expression of proinflammatory cytokines (IL-6 and TNF) and significantly decreasing cell culture density in the laboratory and multidrug-resistant P. aeruginosa strains. ScoBPI was the most potent, with greater anti-inflammatory and bactericidal activity than huBPI and all other orthologues.
This study investigates the action of BPI orthologues as potential CF antimicrobials. While scoBPI appears significantly more effective as an anti-inflammatory and bactericidal agent compared to huBPI, the orthologue has not been tested in environments that model the CF lung environment. The authors describe the cationic BPI as binding to the LPS via electrostatic interaction. This interaction could be limited in vivo, as anionic extracellular DNA, cationic metal ions and polyamines, and other charged substances may impede interaction. Further, delivery of scoBPI to the infection site may be detrimentally impacted, due to the viscous mucous in the lungs and the biofilm mode of growth of P. aeruginosa. The discussion of the study could be improved by describing important considerations for future development. These could include in vitro testing against P. aeruginosa biofilms in relevant sputum-mimicking media, and in vivo validation in Galleria mellonella, and CF and non-CF mouse models.
Overall, the authors present an interesting study that provides a compelling basis for a potential novel antimicrobial for CF chronic airway infection. The authors' claims are well supported by their data, which they present in a clear, logical manner. To build on these findings, the authors could test scoBPI in models that recapitulate core factors of the CF environment.
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Reviewer #2 (Public Review):
Human bactericidal/permeability-increasing protein (huBPI) is known to have in vitro antibacterial activity against Pa, but in vivo, its antibacterial activity is significantly lowered due to binding by autoantibodies called BPI-ANCA. The authors of this study hypothesized that non-human BPIs would escape neutralization by intrinsic BPI-ANCA and retain full antibacterial activity against Pa. Through bioinformatic analysis, the authors anticipated that scorpion BPI (scoBPI) has enough similarity with huBPI to retain antimicrobial activity while escaping recognition by BPI-ANCA. This hypothesis is supported by the following observations: 1) scoBPI fails to capture any BPI-ANCA, 2) scoBPI prevents E. coli- and Pa-LPS dependent inflammatory responses like huBPI and 3) scoBPI exhibits remarkable antimicrobial …
Reviewer #2 (Public Review):
Human bactericidal/permeability-increasing protein (huBPI) is known to have in vitro antibacterial activity against Pa, but in vivo, its antibacterial activity is significantly lowered due to binding by autoantibodies called BPI-ANCA. The authors of this study hypothesized that non-human BPIs would escape neutralization by intrinsic BPI-ANCA and retain full antibacterial activity against Pa. Through bioinformatic analysis, the authors anticipated that scorpion BPI (scoBPI) has enough similarity with huBPI to retain antimicrobial activity while escaping recognition by BPI-ANCA. This hypothesis is supported by the following observations: 1) scoBPI fails to capture any BPI-ANCA, 2) scoBPI prevents E. coli- and Pa-LPS dependent inflammatory responses like huBPI and 3) scoBPI exhibits remarkable antimicrobial activity against MDR-Pa in the nanomolar range. Antimicrobial activity of scoBPI was also demonstrated against E. coli suggesting a conserved mechanism of activity against Gram-negative bacteria. The authors use immobilization methods to demonstrate that scoBPI does not bind BPI-ANCA, but a drawback of this method is that some molecular interactions may be disrupted due to immobilization. Moreover, any inhibitory effects of BPI-ANCA on scoBPI activity in the bactericidal assays were not explored. Regardless, the results of this study clearly support their original hypothesis. These findings have broad implications in identifying novel chemotherapies to treat drug-resistant Gram-negative bacterial infections.
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